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1 Cardiovascular Sciences, Albany Medical College, Albany, NY, USA
* To whom correspondence should be addressed. E-mail: singerh{at}mail.amc.edu.
Activation of ERK1/2 has been implicated in several cellular functions such as gene expression, cell proliferation, and cell migration. We previously reported that in adherent vascular smooth muscle (VSM) cells, Ca2+/calmodulin-dependent protein kinase II
(CaMKII) mediates Ca2+-induced ERK1/2 activation through transactivation of epidermal growth factor receptors. In this study, we tested if CaMKII regulated ERK1/2 signaling in VSM cells in response to cell adhesion. Using an antibody that specifically recognizes CaMKII (auto) phosphorylated on thr287, we determined that CaMKII is rapidly (within 1 min) activated following plating and adherence of cells on multiple substrates, including fibronectin. Adherence on fibronectin resulted in increases in ERK1/2 activation between 30 min and 4 hr. Adhesion-dependent ERK1/2 activation was inhibited by pretreating cells with the selective CaMKII inhibitor KN93 (30 µM) or by suppressing expression of CaMKII
2 with siRNA. Activation of focal adhesion kinase (FAK) was required for adhesion-dependent paxillin tyrosine phosphorylation and ERK1/2 activation as demonstrated by inhibition of the responses in cells overexpressing FAK-related nonkinase(FRNK), an endogenous inhibitor of FAK. Activation of CaMKII was unaffected in cells overexpressing FRNK, indicating that adhesion-dependent CaMKII activation was not dependent on prior activation of FAK. Conversely, adhesion-dependent FAK activation was not affected in cells treated with KN-93 or CaMKII2 siRNA. However, tyrosine phosphorylation of paxillin was inhibited in CaMKII2 suppressed cells. The results indicate that CaMKII2 activation is an early signal during VSM cell adhesion and contributes positively to integrin-dependent signaling pathways resulting in paxillin tyrosine phosphorylation and ERK1/2 activation.
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